Summary: Synapsin, N-terminal domain
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Synapsin Edit Wikipedia article
|Synapsin, N-terminal domain|
Structure of the c domain of synapsin IA from bovine brain.
|Synapsin, ATP binding domain|
The synapsins are a family of proteins that have long been implicated in the regulation of neurotransmitter release at synapses. Specifically, they are thought to be involved in regulating the number of synaptic vesicles available for release via exocytosis at any one time.Synapsins are present in invertebrates and vertebrates and are somewhat homologous across evaluated vertebrates.
Current studies suggest the following hypothesis for the role of synapsin: synapsins bind synaptic vesicles to components of the cytoskeleton which prevents them from migrating to the presynaptic membrane and releasing transmitter. During an action potential, synapsins are phosphorylated by PKA (cAMP dependent protein kinase), releasing the synaptic vesicles and allowing them to move to the membrane and release their neurotransmitter.
Gene knockout studies in mice (where the mouse is unable to produce synapsin) have had some surprising results. Mice lacking all three synapsins are prone to seizures, and experience learning defects. These results suggest that while synapsins are not essential for synaptic function, they do serve an important modulatory role. Conversely, studies using transgenic mice in which neuronal signaling is abolished in specific circuitries showed that synaptic activity regulates, but is not essential to maintain, the expression of these proteins.
Humans and most other vertebrates possess three genes encoding three different synapsin proteins. Each gene in turn is alternatively spliced to produce at least two different protein isoforms for a total of six isoforms:
|SYN1||Synapsin I||Ia, Ib|
|SYN2||Synapsin II||IIa, IIb|
|SYN3||Synapsin III||IIIa, IIIb|
Different neuron terminals will express varying amounts of each of these synapsin proteins and collectively these synapsins will comprise 1% of the total expressed protein at any one time. Synapsin Ia has been implicated in bipolar disorder and schizophrenia.
- Esser L, Wang CR, Hosaka M, Smagula CS, Südhof TC, Deisenhofer J (February 1998). "Synapsin I is structurally similar to ATP-utilizing enzymes". EMBO J. 17 (4): 977–84. doi:10.1093/emboj/17.4.977. PMC 1170447. PMID 9463376.
- Evergren E, Benfenati F, Shupliakov O (September 2007). "The synapsin cycle: a view from the synaptic endocytic zone". J. Neurosci. Res. 85 (12): 2648–56. doi:10.1002/jnr.21176. PMID 17455288.
- Rosahl TW, Geppert M, Spillane D, Herz J, Hammer RE, Malenka RC, Sudhof TC (1993). "Short-term synaptic plasticity is altered in mice lacking synapsin I". Cell 75 (4): 661–670. doi:10.1016/0092-8674(93)90487-B. PMID 7902212.
- Kihara AH, Santos TO, Paschon V, Matos RJ, Britto LR (2008). "Lack of photoreceptor signaling alters the expression of specific synaptic proteins in the retina". Neuroscience 151 (4): 995–1005. doi:10.1016/j.neuroscience.2007.09.088. PMID 18248909.
- Kao HT, Porton B, Hilfiker S, Stefani G, Pieribone VA, DeSalle R, Greengard P (December 1999). "Molecular evolution of the synapsin gene family". J. Exp. Zool. 285 (4): 360–77. doi:10.1002/(SICI)1097-010X(19991215)285:4<360::AID-JEZ4>3.0.CO;2-3. PMID 10578110.
- Gitler D, Xu Y, Kao HT, Lin D, Lim S, Feng J, Greengard P, Augustine GJ (April 2004). "Molecular determinants of synapsin targeting to presynaptic terminals". J. Neurosci. 24 (14): 3711–20. doi:10.1523/JNEUROSCI.5225-03.2004. PMID 15071120.
- Ferreira A, Rapoport M (April 2002). "The synapsins: beyond the regulation of neurotransmitter release". Cell. Mol. Life Sci. 59 (4): 589–95. doi:10.1007/s00018-002-8451-5. PMID 12022468.
- Vawter, MP; et al. (April 2002). "Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia". Mol. Psychiatry 7 (6): 571–8. doi:10.1038/sj.mp.4001158. PMID 12140780.
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This family is structurally related to the PreATP-grasp domain.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR020897
The synapsins are a family of neuron-specific phosphoproteins that coat synaptic vesicles and are involved in the binding between these vesicles and the cytoskeleton (including actin filaments). The family comprises 5 homologous proteins Ia, Ib, IIa, IIb and III. Synapsins I, II, and III are encoded by 3 different genes. The a and b isoforms of synapsin I and II are splice variants of the primary transcripts [PUBMED:10940454].
Synapsin I is mainly associated with regulation of neurotransmitter release from presynaptic neuron terminals [PUBMED:2859595]. Synapsin II, as well as being involved in neurotransmitter release, has a role in the synaptogenesis and synaptic plasticity responsible for long term potentiation [PUBMED:7777057]. Recent studies implicate synapsin III with a developmental role in neurite elongation and synapse formation that is distinct from the functions of synapsins I and II [PUBMED:10804215].
Structurally, synapsins are multidomain proteins, of which 3 domains are common to all the mammalian forms. The N-terminal `A' domain is ~30 residues long and contains a serine residue that serves as an acceptor site for protein kinase-mediated phosphorylation. This is followed by the `B' linker domain, which is ~80 residues long and is relatively poorly conserved. Domain `C' is the longest, spanning approximately 300 residues. This domain is highly conserved across all the synapsins (including those from Drosophila) and is possessed by all splice variants. The remaining six domains, D-I, are not shared by all the synapsins and differ both between the primary transcripts and the splice variants.
This entry represents the pre-ATP-grasp structural domain found in synapsins, which precedes the ATP-grasp domain. The structure of the pre-ATP-grasp domain consists of alpha/beta/alpha in three layers, and is possibly a rudiment form of the Rossmann-fold. This domain can have a substrate-binding function.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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This superfamily is characterised by bein g the copies of the domain that precedes the ATP-grasp domain common to all superfamily members, and it can contain a substrate-binding function.
The clan contains the following 7 members:Biotin_carb_N Dala_Dala_lig_N DUF1246 GARS_N GSH_synth_ATP GSH_synthase Synapsin
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Previous IDs:||Synapsin; Synapsin_N;|
|Author:||Mian N, Bateman A, Griffiths-Jones SR|
|Number in seed:||37|
|Number in full:||245|
|Average length of the domain:||95.10 aa|
|Average identity of full alignment:||57 %|
|Average coverage of the sequence by the domain:||19.14 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Synapsin domain has been found. There are 20 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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